Synthesis of indolylmethyl-hydantoin



2,893,997 Patented July 7, 1959 ana 2,893,997 SYNSIS F mnoLYLumrHYL-nYnANToIN James N. Colrer and Melvin Fields, Wilmington, DeL, andArthur 0. Rogers, Lewiston, N.Y., assignors to E. I. din Pont de Nemoursand Company, Wilmington, Del, a corporation of Delaware No Drawing.Application February 21, 1958 Serial No. 716,550

3 Claims. (Cl. 260-3095) This invention relates to the preparation ofhydantoins and is more particularly concerned with a new route to 5-3-indolylmethyl) -hydantoin.

In our application Serial No. 684,416, filed September 17, 1957, it isdisclosed that 3-indoleacetaldehyde hydrazones such as3-indoleacetaldehyde semicarbazone or 3-indoleacetaldehydephenylhydrazone, or their l-acetyl derivatives, are converted to5-(3-indolylmethyD-hydan- The hybe prepared from 3-indoleacetaldehyde orfrom 3-indoleacetonitrile. The hydrazone has a 3-indolylmethyl groupattached to a carbon which is doubly bonded to a single nitrogen atom ofthe h group of the compound. It has desired conversion place when the3-indolylmethyl group is attached to car- CHBOH In the process of thisinvention the 1,3-diphenyl-2-(3'- ndolylmethyl) -imidazolidine or1,3-diphenyl-2-( 1'-acetyl- '-indolylmethyl)-imidazolidine is heated inan inert olar solvent, preferably water or a lower alcohol or a lixturethereof, containing ammonium ions, carbonate )ns and cyanide ions.Ammonium carbonate and hyrogen cyanide are the most convenient sourcesof the :quired ions, but other materials can obviously be used formthese ions in solution. Thus carbon dioxide and mnonia or variousammonium salts can be added sepately, in place of ammonium carbonate,and metal 'anides can be used in place of hydrogen cyanide. )lid carbondioxide can be added to increase the conntration of carbon dioxide insolution. The addition a small amount of sodium hydrogen sulfite orother perature of about 40 C. is suitable, With pressure being requiredat the higher temperatures. The optimum reaction temperature is 100 to150 C. At about 100 C. the reaction is usually complete in about 3 to 4hours. The relatively insoluble hydantoin product can be recovered byconcentrating the reaction mixture, dissolving the salts in a solventand filtering off the product. The yield can frequently be improved byconcentrating the filtrate or salting out soluble product with neutralsalts, e.ig., sodium sulfate. The hydantoin is purified byrecrystallization from water or other solvent.

The 1,3 diphenyl 2-(3'-indolylmethyl)-imidazolidine and l,3-diphenyl-2-(l'-acetyl-3'-indolylmethyl) -imidazolidine used as starting materials inthe process of this invention may be prepared as described by H.Plieninger and G. Werst, Chem. Ber., 88, 1956 (1955) and 89, 2783(1956).

In the following examples, which illustrate preferred embodiments of theinvention, parts are by weight:

Example 1 This water-insoluble solid was then extracted with hot benzene(150 parts) to remove regenerated N,N-diphenylethylenediamine. Thebenzeneinsoluble material (10.3 parts, yield, of5-(3-indolylmethyDhydantoin) melted at 2l3219 C. The product waspurified by recrystallization from methanol and then from water to giveivory white needles melting at 220- 223 0; this material gave the sameX-ray diffraction pattern as authentic 5(3-indolylmethyl)-hydantoin.

Analysis. Found: C, 6 .73, 62.95; H, 4.91, 4.87; N, 18.49, 1857.Calculated for C H N O z C, 62.88; H, 4.83; N, 18.33.

Example 2 1,3 diphenyl 2-(1'-acetyl-3'-indolylmethyl)-irnidazolidine (30parts), ammonium carbonate (60 parts), hydrogen cyanide (approximately20 parts), sodium bisulfite (1 part), methanol (300 parts) and water(300 parts) were charged into a Hastelloy B tube and heated at for 4hours with shaking. The reaction mixture was then cooled to 0-5discharged and taken to dryness in a Rinco evaporator under aspiratorvacuum, The residue after extraction with three 5-part portions of dryether was obtained as a light yellow solid in a yield of 4 parts. It wasobtained as pale yellow needles, M.P. 215218, from methanol. Thisrecrystallized product did not depress appreciably the melting point(218-219") of an authentic sample of 5-(3-indolylmethyl) -hydantoin.

Since many different embodiments of may be made Without departing fromthe spirit and scope thereof, it is to be understood that the inventionis not limited by the specific illustrations except to the extentdefined in the following claims.

We claim:

1. The process for producing 5-(3-indolylmethyl)-hydantoin whichcomprises reacting a compound selected the invention from the groupconsisting of 1,3-diphenyl-2-(3-indolylmethyl)-imidazolidine and1,3-diphenyl-2-(l-acety1-3- indolylmethyl)-imidazolidine, with ammoniumions, carbonate ions and cyanide ions in an inert polar liquid a solventat 40 to 220 C.

2. The process for producing 5-(3-indolylmethyl)- hydantoin whichcomprises heating a mixture of1,3-diphenyl-2-(S-indolylmethyl)-imadazolidine and a solution containingammonium ions, carbonate ions and cyanide ions in an inert polar liquidsolvent at 40 to 220 C., and recovering the 5-(3-indolylmethyl)-hydantoin formed from the reaction mixture.

3. The process for producing S-(3-indolylmethyl)- hydantoin whichcomprises heating a mixture of 1,3-diphenyl-2-(1-acety1-3'-indolylmethyl) -imidazolidine and a solution containingammonium ions, carbonate ions and cyanide ions in an inert polar liquidsolvent at 40 to 220 C., and recovering the 5-(3ind0lylrnethyl)-hydantoin formed from the reaction mixture.

References Cited in the file of this patent FOREIGN PATENTS

1. THE PROCESS FOR PRODUCING 5-(3-INDOLYLMETHYL)-HYDANTION WHICHCOMPRISES REACTING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF1,3-DIPHENYL-1,2(3''-INDOLYLMETHYL)-IMIDAZOLIDINE AND1,3-DIPHENYL-2(1''-ACETYL-3-''INDOLYMETHYL)-IMIDAZOLIDINE, WITH AMMONIUMIONS, CARBONATE IONS AND CYANIDE IONS IN AN INERT POLAR LIQUID SOLVENTAT 40* TO 220*C.